ABSTRACT ? Project 1 (Leader: Dr. Ann Chahroudi, Emory University) Worldwide, there are currently 1.8 million children living with HIV and ~150,000 new pediatric infections per year, approximately half of which occur due to HIV transmission during breastfeeding. While antiretroviral therapy (ART) greatly reduces mortality and morbidity of HIV infection, viral rebound quickly ensues if ART is interrupted. Understanding the virologic and immunologic drivers of HIV rebound and identifying biomarkers that predict rebound is essential for the design and evaluation of interventions that aim to achieve HIV remission. Inducing HIV remission in infected infants is a highly sought-after outcome, given the fact infected infants currently must remain on daily ART from the time of diagnosis through their entire life span. The overall goal of this Program project application is to investigate virus rebound in the setting of postnatal breast milk transmission in a highly relevant animal model. The objectives of Project 1 are i) to determine the anatomic sources of the persistent virus reservoir in infants that contribute to rebound following treatment interruption, and ii) to identify virologic and immunologic biomarkers that predict the time to virus rebound in infants. The central hypothesis is that virus rebound in SHIV-infected infant rhesus macaques originates from CD4+ T cell subsets in the gastrointestinal tract and/or associated lymph nodes and that on-ART biomarkers can be used as a surrogate indicator of virus rebound kinetics. A key feature of this proposal is that, by using our novel, highly relevant animal model of SHIV infection and ART treatment, we are able to perform in-depth analyses of virus reservoirs and treatment interruption that would be impossible to conduct in pediatric participants. Project 1 has the following Specific Aims: 1) To define the kinetics and anatomic origin of virus rebound in orally SHIV-infected animal model; 2) To identify signature sequences of virus variants in cellular and anatomic reservoirs on ART that contribute to rebound viremia following treatment interruption in our animal model; and 3) To identify virologic and immunologic biomarkers that predict the time to virus rebound in our animal model. This Project will achieve these Aims through interaction with all other Program components, and thus will contribute to the Program's goal to inform design of strategies to induce prolonged remission in postnatally infected infants. We expect the findings from this Project and the Program as a whole to critically inform HIV cure efforts in the pediatric population.